Electropharmacological and Proarrhythmic Effects of a Class III Antiarrhythmic Drug Nifekalant Hydrochloride Assessed Using the In Vivo Canine Models

Cardiovascular effects of Nifekalant were examined using halothane-anesthetized dogs, and its proarrhythmic potential was estimated with chronic complete atrioventricular block dogs. Nifekalant was intravenously administered to the halothane-anesthetized dogs in three doses of 0.03, 0.3, and 3 mg/kg/10 minutes with a pause of 20 minutes (n = 6). The low dose hardly affected any of the cardiovascular parameters. The middle dose, a clinically recommended antiarrhythmic dose, decreased the total peripheral resistance, increased the cardiac output, and prolonged the ventricular repolarization phase and effective refractory period. The high dose increased the left ventricular contraction, transiently decreased the mean blood pressure, and enhanced the atrioventricular conduction, besides potentiation of the changes induced by the middle dose. Increment in the repolarization phase by the high dose was greater than that in the refractoriness, leading to increase of ventricular electrical vulnerability. To the atrioventricular block animals, clinically relevant antiarrhythmic dose of 3 mg/kg p.o. of Nifekalant and its 10-times-higher dose were administered. The high dose prolonged QT interval leading to torsades de pointes in all animals (n = 5), which was not detected by the clinical dose (n = 5). These results suggest that antiarrhythmic dose of Nifekalant can be used safely; however, caution should be paid for patients complicating bradycardia and/or a risk of elevated plasma drug concentration.